The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis.
Kouhei ShimizuHidefumi FukushimaKohei OguraEvan C LienNaoe Taira NihiraJinfang ZhangBrian J NorthAilan GuoKatsuyuki NagashimaTadashi NakagawaSeira HoshikawaAsami WatahikiKoji OkabeAya YamadaAlex TokerJohn M AsaraSatoshi FukumotoKeiichi I NakayamaKeiko NakayamaHiroyuki InuzukaWenyi WeiPublished in: Science signaling (2017)
The SCFβ-TRCP E3 ubiquitin ligase complex plays pivotal roles in normal cellular physiology and in pathophysiological conditions. Identification of β-transducin repeat-containing protein (β-TRCP) substrates is therefore critical to understand SCFβ-TRCP biology and function. We used a β-TRCP-phosphodegron motif-specific antibody in a β-TRCP substrate screen coupled with tandem mass spectrometry and identified multiple β-TRCP substrates. One of these substrates was Lipin1, an enzyme and suppressor of the family of sterol regulatory element-binding protein (SREBP) transcription factors, which activate genes encoding lipogenic factors. We showed that SCFβ-TRCP specifically interacted with and promoted the polyubiquitination of Lipin1 in a manner that required phosphorylation of Lipin1 by mechanistic target of rapamycin 1 (mTORC1) and casein kinase I (CKI). β-TRCP depletion in HepG2 hepatocellular carcinoma cells resulted in increased Lipin1 protein abundance, suppression of SREBP-dependent gene expression, and attenuation of triglyceride synthesis. Moreover, β-TRCP1 knockout mice showed increased Lipin1 protein abundance and were protected from hepatic steatosis induced by a high-fat diet. Together, these data reveal a critical physiological function of β-TRCP in regulating hepatic lipid metabolic homeostasis in part through modulating Lipin1 stability.
Keyphrases
- high fat diet
- binding protein
- gene expression
- tandem mass spectrometry
- transcription factor
- adipose tissue
- genome wide
- type diabetes
- signaling pathway
- high performance liquid chromatography
- dna methylation
- amino acid
- high throughput
- ultra high performance liquid chromatography
- metabolic syndrome
- gas chromatography
- small molecule
- electronic health record
- skeletal muscle
- data analysis
- high fat diet induced